Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). Our project is aimed at understanding and blocking the conversion of normal PrP (PrP-sen) to PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. We have employed a wide variety of cell biological, biochemical, biophysical and in vivo experimental approaches. Over the last year we have 1) developed a high throughput scrapie-infected neuroblastoma cell based screen for inhibitors of PrP-res formation, 2) screened >2000 compounds (natural products or drugs approved for other purposes) and identified ~258 new inhibitors, 17 of which are highly potent against 2 different scrapie strains, 3) begun testing these and other inhibitors for prophylactic and therapeutic activities against scrapie in animals, 4) determined that several inhibitors of PrP-res formation can induce conformational changes, aggregation and fibril formation in recombinant PrP-sen, 5) developed a new type of scrapie-infected neuronal cell line (SN56), 6) obtained initial evidence that laminin binding to normal PrP impedes its conversion to PrP-res, 7) identified a strain-specific and metal-ion dependent folding domain of PrP-res, 8) isolated the minimal oligomeric units of PrP-res between 100-300 kD that retain the protease-resistant and conversion-inducing properties of PrP-res and 8) transmitted and adapted chronic wasting disease from deer and elk to hamsters and transgenic mice expressing hamster PrP-sen.